Background The envelope glycoprotein of the human (HIV) and related simian (SIV) immunodeficiency virus are synthesized as gp160 precursors which are processed into two non-covalently associated glycoproteins: gp120 and gp41. The gp120 mediates viral entry into the host cell by binding to the cellular receptor CD4 and a chemokine coreceptor, both of which are located on the host cell surface. This binding induces conformational changes in the transmembrane gp41, which facilitates membrane fusion between the viral and host membranes. An understanding of these processes in molecular detail may lead to directed and novel means of inhibiting HIV infection. As HIV pg41, and the closely related SIV gp41, are heavily glycosylated transmembrane proteins determination of their high-resolution structures is a very difficult problem. In an incremental approach, we are attempting to study the structure of (non-glycosylated) functional domains of gp41. The most important region of gp41 is the ectodomain region, located on the outer surface of the viral membrane, which directly mediates membrane fusion events. Both HIV and SIV gp41 ectodomains have been expressed in E.coli. The recombinant-produced proteins are suited for structural and biophysical investigations. Results High-resolution X-ray (Hyde/Wang) and NMR (Clore/Gronenborn/Caffrey) structures of the SIV gp41 ectodomain have been determined. The structure determined by both methods is a rod-like trimer comprising three parallel N-terminal a-helices assembled as a coiled-coil in the center with three antiparallel C-terminal a-helices packed on the outside with highly flexible loops connecting the inner and outer helices. The loop region connecting the inner and outer helices, although not clearly resolved in the X-ray model, has been modeled in the NMR structure allowing the connectivity's between inner and outer helices to be established. An analytical ultracentrifugation study demonstrated that gp41 in solution exhibits reversible self-association between a monomer and trimer. This was also confirmed by NMR mixing experiments using differentially labeled protein samples (Caffrey). Other functional regions of the gp41 protein have been expressed in bacteria, including the cytoplasmic domain, we now characterizing these proteins with the intention of using them for additional structural studies. Significance and future direction The high-resolution structure determinations of the gp41 ectodomain will allow a more rational approach to the design of novel peptide inhibitors. Based on the physical properties of the gp41, models of membrane fusion have been proposed which involve partially associated protein complexes. These models may also provide useful clues for targeting gp41. A more complete picture of membrane fusion will require more extensive structural work on gp41, especially those regions involved in mediating interaction with gp120. The expression of various engineered gp120 proteins, including the N- and C-terminal dominants which are thought to interact with gp41, are being made for bacterial expression. Summary Envelope proteins on the surface of the human immunodeficiency virus (HIV) which mediate entry of the virus into its host cell have been expressed in bacteria using recombinant DNA methods. The envelope proteins were purified and their structures studied. It is hoped that an understanding of the molecular details of these proteins, vital for the viral life cycle, will aid in the development of reagents and methods for blocking their function.